Ultrasound is a broadly used tool in medical imaging and it has several advantages over other imaging techniques such as MRI and computed tomography (“CT”). Ultrasound is a real-time, nonionizing, cost effective, portable, and widely available imaging modality. Ultrasound contrast agents have enabled researchers to expand their investigations into molecular scales, contributing to increased contrast enhancement and also contrast-specific imaging. The most common ultrasound contrast agents, composed of specific gaseous microbubbles in a core shell, have been investigated to enhance contrast in ultrasound medicine. Compared to the surrounding tissue, microbubbles present a large acoustic impedance mismatch in tissues and thus produce a strong backscattered sound signal. In addition, microbubbles are used in harmonic and subharmonic imaging to improve the subjective image quality. Although microbubbles play an important role in increasing the enhancement of the diagnostic potential of ultrasound imaging, the micron-sized bubbles have limited use in molecular imaging because these agents are too large to pass through the pulmonary and systemic capillary bed. Moreover, microbubbles are unstable, have a short blood half-life and a propensity to fracture and collapse when exposed to ultrasound waves. Furthermore, microbubbles need sufficient acoustic pressure to increase contrast. These features have limited the use of microbubbles in ultrasound molecular imaging. To overcome the size effects and increase the efficacy of enhancement imaging, perfluorocarbon emulsion nanoparticles (“PFC”), approximately 250 nm in diameter, were reported as an alternative ultrasound contrast agent. Nanometer-sized ultrasound contrast agents may penetrate the large capillary bed, but penetration to vascular targets and extravasations through tight capillary pores could be inhibited due to their relatively large size. Unfortunately, PFC ultrasound contrast agents produced a smaller acoustic impedance mismatch, a weaker ultrasound reflected signal, and create less contrast enhancement of echogenic images than gaseous microbubbles.
Superparamagnetic iron oxide (“SPIO”) nanoparticles have been well established over the past decade as a contrast enhancement for MRI imaging. Early studies demonstrated that SPIO nanoparticles can improve the detection of liver metastases in patients. After SPIO nanoparticles have been administrated intravenously, tissue-based macrophages (Kupffer cells) in the body take up SPIO nanoparticles through the reticulo endothelial system (“RES”) including bone marrow, hepatic lesions, lymph node metastases in cancer, and spleen. Compared to conventional ultrasound contrast agents, magnetically activated SPIO nanoparticles have several advantages, including small size, strong magnetic susceptibility, and bio-safety. These nanoparticles (μ20 nm core size) allow transport through the microvasculature and enable passage through the endothelium while retaining their super paramagnetic properties. Since SPIO nanoparticles for tissue-specific MRI contrast agents were approved by the FDA in 1996, to date, these magnetic nanoparticles have been used in various clinical applications without safety concerns associated with alternative contrast agents.
The present application improves ultrasound imaging.